Genetically modified non-human animal with human or chimeric genes

Abstract

The present disclosure relates to genetically modified non-human animals that express a human or chimeric (e.g., humanized) IL2RG, IL2RB, IL15RA, and/or IL15, and methods of use thereof.

1 . A genetically-modified, non-human animal whose genome comprises at least one chromosome comprising a sequence encoding a human or chimeric Interleukin 2 Receptor Subunit Gamma (IL2RG). 
     
     
         2 . The animal of  claim 1 , wherein the sequence encoding the human or chimeric IL2RG is operably linked to an endogenous regulatory element at the endogenous IL2RG gene locus in the at least one chromosome. 
     
     
         3 . The animal of  claim 1 or 2 , wherein the sequence encoding a human or chimeric IL2RG comprises a sequence encoding an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to human IL2RG (NP_000197.1 (SEQ ID NO: 2)). 
     
     
         4 . The animal of  claim 1 or 2 , wherein the sequence encoding a human or chimeric IL2RG comprises a sequence encoding an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 30. 
     
     
         5 . The animal of  claim 1 or 2 , wherein the sequence encoding a human or chimeric IL2RG comprises a sequence encoding an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to amino acids 1-256 of SEQ ID NO: 2. 
     
     
         6 . The animal of any one of  claims 1-5 , wherein the animal is a mammal, e.g., a monkey, a rodent, a mouse, or a rat. 
     
     
         7 . The animal of any one of  claims 1-6 , wherein the animal does not express endogenous IL2RG or expresses a decreased level of endogenous IL2RG as compared to IL2RG expression level in a wild-type animal. 
     
     
         8 . The animal of any one of  claims 1-7 , wherein the animal has one or more cells expressing human or chimeric IL2RG. 
     
     
         9 . The animal of any one of  claims 1-8 , wherein the animal has one or more cells expressing human or chimeric IL2RG, and the expressed human or chimeric IL2RG can interact with human or endogenous Interleukin-2 Receptor Subunit Alpha (IL2RA) and Interleukin 2 Receptor Subunit Beta (IL2RB), forming a functional IL2 receptor complex. 
     
     
         10 . The animal of any one of  claims 1-8 , wherein the animal has one or more cells expressing human or chimeric IL2RG, and the expressed human or chimeric IL2RG can interact with human or endogenous Interleukin-15 Receptor Subunit Alpha (IL15RA) and Interleukin 2 Receptor Subunit Beta (IL2RB), forming a functional IL15 receptor complex. 
     
     
         11 . A genetically-modified, non-human animal, wherein the genome of the animal comprises a replacement of a sequence encoding a region of endogenous IL2RG with a sequence encoding a corresponding region of human IL2RG at an endogenous IL2RG gene locus. 
     
     
         12 . The animal of  claim 11 , wherein the sequence encoding the corresponding region of human IL2RG is operably linked to an endogenous regulatory element at the endogenous IL2RG locus, and one or more cells of the animal expresses a human or chimeric IL2RG. 
     
     
         13 . The animal of  claim 11 or 12 , wherein the animal does not express endogenous IL2RG or expresses a decreased level of endogenous IL2RG as compared to IL2RG expression level in a wild-type animal. 
     
     
         14 . The animal of any one of  claims 11-13 , wherein the replaced sequence encodes the full-length IL2RG; or the signal peptide and all or a portion of the extracellular region of IL2RG. 
     
     
         15 . The animal of any one of  claims 11-14 , wherein the animal has one or more cells expressing human IL2RG. 
     
     
         16 . The animal of any one of  claims 11-14 , wherein the animal has one or more cells expressing a chimeric IL2RG having a signal peptide, an extracellular region, a transmembrane region, and a cytoplasmic region, wherein the extracellular region comprises a sequence that is at least 50%, 60%, 70%, 80%, 90%, 95%, or 99% identical to the extracellular region of human IL2RG (NP_000197.1 (SEQ ID NO: 2)). 
     
     
         17 . The animal of  claim 16 , wherein the extracellular region of the chimeric IL2RG has a sequence that has at least 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, or 240 contiguous amino acids that are identical to a contiguous sequence present in the extracellular region of human IL2RG (e.g., amino acids 23-256 or 23-262 of SEQ ID NO: 2). 
     
     
         18 . The animal of  claim 16 or 17 , wherein the signal peptide of the chimeric IL2RG has a sequence that has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 contiguous amino acids that are identical to a contiguous sequence present in the signal peptide of human IL2RG (e.g., amino acids 1-22 of SEQ ID NO: 2). 
     
     
         19 . The animal of any one of  claims 11-18 , wherein the sequence encoding a region of endogenous IL2RG (e.g., mouse IL2RG) comprises exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, and/or exon 8 (e.g., exon 1, exon 2, exon 3, exon 4, exon 5, and exon 6), or a part thereof, of the endogenous IL2RG gene. 
     
     
         20 . The animal of any one of  claims 11-19 , wherein the animal is heterozygous or homozygous with respect to the replacement at the endogenous IL2RG gene locus. 
     
     
         21 . A non-human animal comprising at least one cell comprising a nucleotide sequence encoding a human or humanized IL2RG polypeptide, wherein the human or humanized IL2RG polypeptide comprises at least 50 contiguous amino acid residues that are identical to the corresponding contiguous amino acid sequence of a human IL2RG, wherein the animal expresses the human or humanized IL2RG polypeptide. 
     
     
         22 . The animal of  claim 21 , wherein the human or humanized IL2RG polypeptide has at least 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 231, 232, 233, 234, 235, 236, 237, 238, 239, or 240 contiguous amino acid residues that are identical to the corresponding contiguous amino acid sequence of human IL2RG extracellular region (e.g., amino acids 23-256 or 23-262 of SEQ ID NO: 2). 
     
     
         23 . The animal of  claim 21 or 22 , wherein the human or humanized IL2RG polypeptide has at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, or 22 contiguous amino acid residues that are identical to the corresponding contiguous amino acid sequence of human IL2RG signal peptide (e.g., amino acids 1-22 of SEQ ID NO: 2). 
     
     
         24 . The animal of any one of  claims 21-23 , wherein the human or humanized IL2RG polypeptide comprises a sequence that is at least 90%, 95%, or 99% identical to amino acids 1-256 or 1-262 of SEQ ID NO: 2. 
     
     
         25 . The animal of any one of  claims 21-24 , wherein the nucleotide sequence is operably linked to an endogenous IL2RG regulatory element of the animal. 
     
     
         26 . The animal of any one of  claims 21-25 , wherein the nucleotide sequence is integrated to an endogenous IL2RG gene locus of the animal. 
     
     
         27 . The animal of any one of  claims 21-26 , wherein the nucleotide sequence encodes a humanized IL2RG polypeptide, wherein the humanized IL2RG polypeptide comprises an endogenous IL2RG transmembrane region and/or an endogenous IL2RG cytoplasmic region. 
     
     
         28 . The animal of  claim 27 , wherein the humanized IL2RG polypeptide has at least one mouse IL2RG activity and/or at least one human IL2RG activity. 
     
     
         29 . A method for making a genetically-modified, non-human animal, comprising:
 replacing in at least one cell of the animal, at an endogenous IL2RG gene locus, a sequence encoding a region of endogenous IL2RG with a sequence encoding a corresponding region of human IL2RG.   
     
     
         30 . The method of  claim 29 , wherein the sequence encoding the corresponding region of human IL2RG comprises exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, and/or exon 8, or a part thereof, of a human IL2RG gene. 
     
     
         31 . The method of  claim 29 or 30 , wherein the sequence encoding the corresponding region of human IL2RG comprises a portion of exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, and exon 8, optionally at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 20, 30, 40, 50, 60, 61, 62, 63, 64, 65, 70, 80, 90, or 100 nucleotides downstream of exon 8, of a human IL2RG gene. 
     
     
         32 . The method of  claim 29 or 30 , wherein the sequence encoding the corresponding region of human IL2RG comprises a portion of exon 1, exon 2, exon 3, exon 4, exon 5, and a portion of exon 6, of a human IL2RG gene. 
     
     
         33 . The method of any one of  claims 29-32 , wherein the sequence encoding the corresponding region of human IL2RG encodes amino acids 1-256, 1-262, or 1-369 of SEQ ID NO: 2. 
     
     
         34 . The method of any one of  claims 29-33 , wherein the region comprises the full-length IL2RG; or the signal peptide and all or a portion of the extracellular region of IL2RG. 
     
     
         35 . The method of any one of  claims 29-34 , wherein the sequence encoding a region of endogenous IL2RG comprises exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, and/or exon 8, or a part thereof, of the endogenous IL2RG gene. 
     
     
         36 . The method of any one of  claims 29-35 , wherein the animal is a mouse, and the sequence encoding a region of endogenous IL2RG comprises a portion of exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, and a portion of exon 8 of the endogenous IL2RG gene. 
     
     
         37 . The method of any one of  claims 29-35 , wherein the animal is a mouse, and the sequence encoding a region of endogenous IL2RG comprises a portion of exon 1, exon 2, exon 3, exon 4, exon 5, and a portion of exon 6 of the endogenous IL2RG gene. 
     
     
         38 . A method of making a genetically-modified animal cell that expresses a chimeric IL2RG, the method comprising:
 replacing at an endogenous IL2RG gene locus, a nucleotide sequence encoding a region of endogenous IL2RG with a nucleotide sequence encoding a corresponding region of human IL2RG, thereby generating a genetically-modified animal cell that includes a nucleotide sequence that encodes the chimeric IL2RG, wherein the animal cell expresses the chimeric IL2RG.   
     
     
         39 . The method of  claim 38 , wherein the chimeric IL2RG comprises a human or humanized IL2RG extracellular region; and a transmembrane and/or a cytoplasmic region of mouse IL2RG. 
     
     
         40 . The method of  claim 39 , wherein the chimeric IL2RG further comprises a human or humanized IL2RG signal peptide. 
     
     
         41 . A method of making a genetically-modified animal cell that expresses a human IL2RG, the method comprising:
 replacing at an endogenous IL2RG gene locus, a nucleotide sequence encoding a region of endogenous IL2RG with a nucleotide sequence encoding a corresponding region of human IL2RG, thereby generating a genetically-modified animal cell that includes a nucleotide sequence that encodes the human IL2RG, wherein the animal cell expresses the human IL2RG.   
     
     
         42 . The method of any one of  claims 38-41 , wherein the animal is a mouse. 
     
     
         43 . The method of any one of  38 - 42 , wherein the nucleotide sequence encoding the chimeric IL2RG is operably linked to an endogenous IL2RG regulatory region, e.g., promoter. 
     
     
         44 . The animal of any one of  claims 1-28 , wherein the animal further comprises a sequence encoding an additional human or chimeric protein, e.g., Interleukin 2 Receptor Subunit Beta (IL2RB), Interleukin 15 (IL15), Interleukin-15 Receptor Subunit Alpha (IL15RA), Interleukin 2 (IL2), Interleukin 2 Receptor Subunit Alpha (IL2RA), programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), Interleukin 10 Receptor Subunit Alpha (IL10RA), and/or cytotoxic T-lymphocyte-associated protein 4 (CTLA4). 
     
     
         45 . The method of any one of  claims 29-43 , wherein the animal or mouse further comprises a sequence encoding an additional human or chimeric protein, e.g., IL2RB, IL15, IL15RA, IL2, IL2RA, PD-1, PD-L1, IL10RA, and/or CTLA4. 
     
     
         46 . A genetically-modified, non-human animal whose genome comprises at least one chromosome comprising a sequence encoding a human or chimeric Interleukin-15 (IL15). 
     
     
         47 . The animal of  claim 46 , wherein the sequence encoding the human or chimeric IL15 is operably linked to an endogenous regulatory element at the endogenous IL15 gene locus in the at least one chromosome. 
     
     
         48 . The animal of  claim 46 or 47 , wherein the sequence encoding a human or chimeric IL15 comprises a sequence encoding an amino acid sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to human IL15 (NP_000576.1 (SEQ ID NO: 52)). 
     
     
         49 . The animal of  claim 46 or 47 , wherein the sequence encoding a human or chimeric IL15 comprises a sequence that is at least 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% identical to SEQ ID NO: 55. 
     
     
         50 . The animal of any one of  claims 46-49 , wherein the animal is a mammal, e.g., a monkey, a rodent, a mouse, or a rat. 
     
     
         51 . The animal of any one of  claims 46-50 , wherein the animal does not express endogenous IL15 or expresses a decreased level of endogenous IL15 as compared to IL15 expression level in a wild-type animal. 
     
     
         52 . The animal of any one of  claims 46-51 , wherein the animal has one or more cells expressing human or chimeric IL15. 
     
     
         53 . The animal of any one of  claims 46-52 , wherein the animal has one or more cells expressing human or chimeric IL15, and the expressed human or chimeric IL15 is functional that can interact with a human, chimeric, or endogenous IL15 receptor complex. 
     
     
         54 . A genetically-modified, non-human animal, wherein the genome of the animal comprises a replacement of a sequence encoding a region of endogenous IL15 with a sequence encoding a corresponding region of human IL15 at an endogenous IL15 gene locus. 
     
     
         55 . The animal of  claim 54 , wherein the sequence encoding the corresponding region of human IL15 is operably linked to an endogenous regulatory element at the endogenous IL15 locus, and one or more cells of the animal expresses a human or chimeric IL15. 
     
     
         56 . The animal of  claim 54 or 55 , wherein the animal does not express endogenous IL15 or expresses a decreased level of endogenous IL15 as compared to IL15 expression level in a wild-type animal. 
     
     
         57 . The animal of any one of  claims 54-56 , wherein the replaced sequence encodes the full-length IL15. 
     
     
         58 . The animal of any one of  claims 54-57 , wherein the sequence encoding a region of endogenous IL15 (e.g., mouse IL15) comprises exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, and/or exon 8 (e.g., exon 3, exon 4, exon 5, exon 6, exon 7, and exon 8), or a part thereof, of the endogenous IL15 gene. 
     
     
         59 . The animal of any one of  claims 54-58 , wherein the animal is heterozygous or homozygous with respect to the replacement at the endogenous IL15 gene locus. 
     
     
         60 . A non-human animal comprising at least one cell comprising a nucleotide sequence encoding a human or humanized IL15 polypeptide, wherein the human or humanized IL15 polypeptide comprises at least 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 161, or 162 contiguous amino acid residues that are identical to the corresponding contiguous amino acid sequence of a human IL15, wherein the animal expresses the human or humanized IL15 polypeptide. 
     
     
         61 . The animal of  claim 60 , wherein the human or humanized IL15 polypeptide comprises a sequence that is at least 90%, 95%, or 99% identical to SEQ ID NO: 52. 
     
     
         62 . The animal of  claim 60 or 61 , wherein the nucleotide sequence is operably linked to an endogenous IL15 regulatory element of the animal. 
     
     
         63 . The animal of any one of  claims 60-62 , wherein the nucleotide sequence is integrated to an endogenous IL15 gene locus of the animal. 
     
     
         64 . A method for making a genetically-modified, non-human animal, comprising:
 replacing in at least one cell of the animal, at an endogenous IL15 gene locus, a sequence encoding a region of endogenous IL15 with a sequence encoding a corresponding region of human IL15.   
     
     
         65 . The method of  claim 64 , wherein the sequence encoding the corresponding region of human IL15 comprises exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, and/or exon 8, or a part thereof, of a human IL15 gene. 
     
     
         66 . The method of  claim 64 or 65 , wherein the sequence encoding the corresponding region of human IL15 comprises a portion of exon 3, exon 4, exon 5, exon 6, exon 7, and a portion of exon 8, of a human IL15 gene. 
     
     
         67 . The method of any one of  claims 64-66 , wherein the sequence encoding the corresponding region of human IL15 encodes SEQ ID NO: 52. 
     
     
         68 . The method of any one of  claims 64-67 , wherein the sequence encoding a region of endogenous IL15 comprises exon 1, exon 2, exon 3, exon 4, exon 5, exon 6, exon 7, and/or exon 8, or a part thereof, of the endogenous IL15 gene. 
     
     
         69 . The method of any one of  claims 64-68 , wherein the animal is a mouse, and the sequence encoding a region of endogenous IL15 comprises a portion of exon 3, exon 4, exon 5, exon 6, exon 7, and a portion of exon 8, of the endogenous IL15 gene. 
     
     
         70 . A method of making a genetically-modified animal cell that expresses a human or humanized IL15, the method comprising:
 replacing at an endogenous IL15 gene locus, a nucleotide sequence encoding a region of endogenous IL15 with a nucleotide sequence encoding a corresponding region of human IL15, thereby generating a genetically-modified animal cell that includes a nucleotide sequence that encodes the human or humanized IL15, wherein the animal cell expresses the human or humanized IL15.   
     
     
         71 . The method of  claim 70 , wherein the animal is a mouse. 
     
     
         72 . The method of  claim 70 or 71 , wherein the nucleotide sequence encoding the human or humanized IL15 is operably linked to an endogenous IL15 regulatory region, e.g., promoter. 
     
     
         73 . The animal of any one of  claims 46-63 , wherein the animal further comprises a sequence encoding an additional human or chimeric protein, e.g., Interleukin 2 Receptor Subunit Beta (IL2RB), Interleukin 2 Receptor Subunit Gamma (IL2RG), Interleukin-15 Receptor Subunit Alpha (IL15RA), Interleukin 2 (IL2), Interleukin 2 Receptor Subunit Alpha (IL2RA), programmed cell death protein 1 (PD-1), programmed death-ligand 1 (PD-L1), Interleukin 10 Receptor Subunit Alpha (IL10RA), and/or cytotoxic T-lymphocyte-associated protein 4 (CTLA4). 
     
     
         74 . The method of any one of  claims 64-72 , wherein the animal or mouse further comprises a sequence encoding an additional human or chimeric protein, e.g., IL2RB, IL2RG, IL15RA, IL2, IL2RA, PD-1, PD-L1, IL10RA, and/or CTLA4. 
     
     
         75 . A method of determining effectiveness of a therapeutic agent for treating an allergic disorder (e.g., allergy, asthma, and/or atopic dermatitis), comprising:
 a) administering the therapeutic agent to the animal of any one of  claims 1-28, 44, 46-63, and 73 , wherein the animal has the allergic disorder; and   b) determining effects of the therapeutic agent in treating the allergic disorder.   
     
     
         76 . A method of determining effectiveness of a therapeutic agent for reducing an inflammation (e.g., skin inflammation or infection), comprising:
 a) administering the therapeutic agent to the animal of any one of  claims 1-28, 44, 46-63, and 73 , wherein the animal has the inflammation; and   b) determining effects of the therapeutic agent for reducing the inflammation.   
     
     
         77 . A method of determining effectiveness of a therapeutic agent for treating an immune disorder, comprising:
 a) administering the agent to the animal of any one of  claims 1-28, 44, 46-63, and 73 , wherein the animal has the immune disorder; and   b) determining effects of the therapeutic agent for treating the immune disorder.   
     
     
         78 . The method of  claim 77 , wherein the immune disorder is psoriasis. 
     
     
         79 . The method of  claim 77 , wherein the immune disorder is an autoimmune disease, e.g., graft versus host disease (GVHD), psoriasis, allergy, asthma, myocarditis, nephritis, hepatitis, systemic lupus erythematosus, rheumatoid arthritis, scleroderma, hyperthyroidism, idiopathic thrombocytopenia purpura, autoimmune hemolytic anemia, ulcerative colitis, autoimmune liver disease, diabetes, pain or neurological disorders. 
     
     
         80 . The method of any one of  claims 75-79 , wherein the therapeutic agent includes an anti-IL2RB antibody, an anti-IL2RG antibody, an anti-IL15RA antibody, and/or an anti-IL15 antibody, or a corticosteroid (e.g., dexamethasone). 
     
     
         81 . A method of determining effectiveness of a therapeutic agent for treating a cancer, comprising:
 a) administering the therapeutic agent to the animal of any one of  claims 1-28, 44, 46-63, and 73 , wherein the animal has the cancer; and   b) determining inhibitory effects of the therapeutic agent for treating the cancer.   
     
     
         82 . The method of  claim 81 , wherein the therapeutic agent includes an anti-IL2RB antibody, an anti-IL2RG antibody, an anti-IL15RA antibody, and/or an anti-IL15 antibody. 
     
     
         83 . The method of  claim 81 or 82 , wherein the cancer is a tumor, and determining the inhibitory effects of the treatment involves measuring the tumor volume in the animal. 
     
     
         84 . The method of any one of  claims 81-83 , wherein the cancer comprises one or more cancer cells that are injected into the animal. 
     
     
         85 . The method of any one of  claims 81-84 , wherein the cancer is breast cancer, ovarian cancer, endometrial cancer, melanoma, kidney cancer, lung cancer, or liver cancer. 
     
     
         86 . A method of determining toxicity of an anti-IL2RB antibody, an anti-IL2RG antibody, an anti-IL15RA antibody, and/or an anti-IL15 antibody, comprising:
 a) administering the anti-IL2RB antibody, the anti-IL2RG antibody, the anti-IL15RA antibody, and/or the anti-IL15 antibody to the animal of any one of  claims 1-28, 44, 46-63, and 73 ; and   b) determining effects of the therapeutic agent to the animal.   
     
     
         87 . The method of  claim 86 , wherein determining effects of the therapeutic agent to the animal involves measuring the body weight, red blood cell count, hematocrit, and/or hemoglobin of the animal. 
     
     
         88 . A protein comprising an amino acid sequence, wherein the amino acid sequence is one of the following:
 (a) an amino acid sequence set forth in SEQ ID NO: 1, 2, 30, 33, 34, 39, 42, 43, 50, 51, or 52;   (b) an amino acid sequence that is at least 90% identical to SEQ ID NO: 1, 2, 30, 33, 34, 39, 42, 43, 50, 51, or 52;   (c) an amino acid sequence that is at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 1, 2, 30, 33, 34, 39, 42, 43, 50, 51, or 52;   (d) an amino acid sequence that is different from the amino acid sequence set forth in SEQ ID NO: 1, 2, 30, 33, 34, 39, 42, 43, 50, 51, or 52 by no more than 10, 9, 8, 7, 6, 5, 4, 3, 2 or 1 amino acid; and   (e) an amino acid sequence that comprises a substitution, a deletion and/or insertion of one, two, three, four, five or more amino acids to the amino acid sequence set forth in SEQ ID NO: 1, 2, 30, 33, 34, 39, 42, 43, 50, 51, or 52.   
     
     
         89 . A nucleic acid comprising a nucleotide sequence, wherein the nucleotide sequence is one of the following:
 (a) a sequence that encodes the protein of claim  88 ;   (b) SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 24, 25, 26, 27, 28, 29, 31, 32, 35, 36, 37, 38, 40, 41, 44, 45, 46, 47, 48, 49, 53, 54, 55, 56, 57, or 58;   (c) a sequence that is at least 90% identical to SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 24, 25, 26, 27, 28, 29, 31, 32, 35, 36, 37, 38, 40, 41, 44, 45, 46, 47, 48, 49, 53, 54, 55, 56, 57, or 58; and   (d) a sequence that is at least 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to SEQ ID NO: 3, 4, 5, 6, 7, 8, 9, 24, 25, 26, 27, 28, 29, 31, 32, 35, 36, 37, 38, 40, 41, 44, 45, 46, 47, 48, 49, 53, 54, 55, 56, 57, or 58.   
     
     
         90 . A cell comprising the protein of  claim 88  and/or the nucleic acid of  claim 89 . 
     
     
         91 . An animal comprising the protein of  claim 88  and/or the nucleic acid of  claim 89 .